Is Metformin a Therapeutic Paradigm for Colorectal Cancer: Insight into the Molecular Pathway?

Abstract

Colorectal cancer (CRC) remains one of the major leading causes of cancer related morbidity and mortality. Apart from the conventional anti-neoplastic agents, metformin, a biguanide anti-diabetic agent, has recently found to have anti-cancer property. Several studies observed the effect of metformin towards its anti-cancer effect on colon or colorectal cancer in diabetic patients. However, only a few studies showed its effect on colorectal cancer in relation to the non-diabetic status. The present review aimed to highlight the insight into the molecular pathway of metformin towards colorectal cancer in the absence of diabetes mellitus. In CRC-independent of diabetes mellitus, highly deregulation of PI3K/AKT pathway is found which activates the downstream mammalian target of rapamycin (mTOR). Metformin inhibits cancer growth in colon by suppressing the colonic epithelial proliferation by inhibiting the mTOR pathway. Metformin exerts its anti-neoplastic effects by acting on tumour suppressor pathway via activating the adenosine monophosphate.activated protein kinase (AMPK) signaling pathway. Metformin interrupts the glucose metabolism by activating the AMPK. Metformin reduces tumour cell growth and metastasis by activating the p53 tumour suppressor gene. In addition to its therapeutic benefits, metformin is easily accessible, cost effective with better tolerance to the patients compared to the chemotherapeutic agents. This review summarised modern findings on the therapeutic applications of metformin on the colorectal cancer with no evidences of diabetes mellitus.

Knockdown of KLK12 inhibits viability and induces�apoptosis in human colorectal cancer HT-29 cell line

“…Mammalian target of rapamycin (mTOR) is also a serine/threonine protein kinase that regulates cell growth by integrating nutrient and growth factor signaling (11). Numerous studies have indicated that rapamycin may inhibit the proliferation of colorectal cancer cells in vivo and in vitro , and it has been suggested that the mTOR pathway is activated in patients with colorectal cancer (12,13). Therefore, targeting AMPK and mTOR signal pathways may be a promising protective strategy for management of colorectal cancer.…”

Long non-coding RNA LINC00261 sensitizes human colon cancer cells to cisplatin therapy

“…Colon cancer has been reported to be one of the most common malignant tumors in the digestive system, and has high morbidity and mortality rates ( 1 , 2 ). A large number of studies have shown that dietary habits, induced inflammation and other factors such as genetic mutations can lead to the occurrence of colorectal cancer ( 3 – 5 ).…”

Metformin inhibited colitis and colitis-associated cancer (CAC) through protecting mitochondrial structures of colorectal epithelial cells in mice

“…There are evidence in vitro and in vivo studies that metformin has been considered a cancer chemotherapeutic agent. 4,5 Many clinical trials have been performed to investigate the inhibitory effects of metformin alone or in combination with other drugs on various cancers. Currently, two major pathways are recognized as the main ways in which metformin exerts its antitumor effect.…”

“…2,3 Metformin is currently used extensively in the treatment of type 2 diabetes mellitus (T2DM), but there is potential for additional indications in many other diseases, such as inflammatory disorders and cancers. [4][5][6][7] Epidemiological studies revealed an association between the use of metformin and decreased incidence of many types of cancers. 8,9 Diabetic patients taking metformin showed a decreased incidence of pancreatic cancer.…”